Process for producing erythromycin derivative

ABSTRACT

There is provided a preparation process useful for an efficient synthesis of 6-O-substituted ketolide derivatives by combining a characterized step of introduction of a substituent at the 6-position by selective cleavage of a C—O bond of the cyclic acetal at the 9-position side via 6,9-cyclic acetal 5-O-desosaminyl erythronolide derivative, a step of conversion into carbonyl groups at the 9- and 3-positions, and a step of 11,12-cyclic carbamation to lead to 6-O-substituted ketolide derivatives.

TECHNICAL FIELD PERTINENT TO THE INVENTION

The present invention relates to processes for preparing erythromycinderivatives and to intermediates thereof, and particularly relates to aprocess for preparing 6-O-substituted ketolide derivatives starting fromerythromycin and to intermediates thereof.

PRIOR ART

Macrolide antibiotics including erythromycin A have a strongantibacterial activity against Gram-positive bacteria, someGram-negative bacteria, Mycoplasmas and the like, and have been widelyused as agents for the treatment of infections caused by these bacteria.Furthermore, many erythromycin derivatives have been synthesized for thepurpose of the improvement of pharmacokinetic properties of erythromycinA, and some of them have already been clinically used as excellentantibiotics. For example, clarithromycin (6-O-methylerythromycin A, U.S.Pat. No. 4,331,803) has been widely used as a therapeutic agent ofrespiratory tract infections due to its excellent biological properties.There has been recently reported the derivatives which are genericallycalled ketolides and have a potent antibacterial activity againstmacrolide-resistant bacteria. The structural features of thesederivatives are such that the cladinose group at the 3-position oferythromycin A has been removed, and converted into a carbonyl group,the hydroxyl group at the 6-position has been alkylated, and thehydroxyl groups at the 11- and 12-postions have been converted into acyclic carbamate. Among these ketolides, there is3-deoxy-3-oxo-6-O-((3-quinol-3-yl)prop-2-enyl)-5-O-desosaminylerythronolide A 11,12-cyclic carbamate (U.S. Pat. No. 5,866,549, and J.Medicinal Chemistry, vol. 43, pp.1045-1049 (2000)), which has a strongantibacterial activity against both of macrolide-sensitive andmacrolide-resistant bacteria that cause respiratory tract infections. Asmentioned above, this compound is prepared by modifying at threepositions, i.e., at the 6-, 3- and 11,12-positions. The preparationprocess reported is carried out by once converting the carbonyl group atthe 9-position into an oxime derivative, modifying at the 6-position andreproducing a carbonyl group at the 9-position, therefore thismanufacturing process needs many steps, and is complicated.

Problems to be Solved by the Invention

An object of the present invention is to provide processes for preparingerythromycin derivatives and intermediates thereof, and moreparticularly to provide preparation processes useful for an efficientsynthesis of a 6-O-substituted ketolide derivative.

Means for Solving the Problems

As a result of diligently studies, the present inventors have found aprocess for leading to a 6-O-substituted ketolide derivatives, whichcomprises combining a characterized step of introduction of asubstituent at the 6-position by selective cleavage of the C—O bond ofthe cyclic acetal at the 9-position side via a 6,9-cyclic acetal5-O-desosaminyl erythronolide derivative, a step of conversion intocarbonyl groups at the 9- and 3-positions, and a step of 11,12-cycliccarbamation, thereby the present invention have been accomplished.Specifically, this process is useful as a process for the synthesis of3-deoxy-3-oxo-6-O-((3-quinol-3-yl)prop-2-enyl)-5-O-desosaminylerythronolide A 11,12-cyclic carbamate which has been recently reportedto have a potent antibacterial activity, and the like.

That is, the present invention is directed to a process for preparingCompound (V) defined below, which comprises the steps of:

(A) providing Compound (I) of the formula:

wherein R₁ and R₂, which may be the same or different, are a hydrogenatom, formula —CO—R_(A) wherein R_(A) is a C₁₋₃ alkyl group, C₁₋₃ alkylgroup substituted with 1-3 halogen atoms, C₁₋₃ alkoxy group, phenylgroup, phenyloxy group, benzyloxy group, or phenyl group substitutedwith 1-3 atoms/substituents selected from the group consisting of C₁₋₃alkyl group, C₁₋₃ alkoxy group, nitro group, cyano group, halogen atom,acetyl group, phenyl group and hydroxy group, or a silyl groupsubstituted with 2-3 substituents selected from the group consisting ofC₁₋₄ alkyl group, phenyl group and benzyl group,

by reaction of erythromycin with ethylene carbonate, subsequentreduction of ketone in 9-position, and optional protection of hydroxygroups in 2′- and/or 4″-positions,

(B) reacting Compound (I) with a compound of the formula:

wherein A is CH═CH or C≡C; R₅ and R₆, which may be the same ordifferent, are a C₁₋₇ alkyl group,

and optionally protecting a resulting 3-hydroxy group, to obtainCompound (II) of the formula:

wherein R₃ is the same as R₁ defined above; R₂ and A are as definedabove,

(C) reacting Compound (II) with a compound of the formula:

X—R₄  (2)

wherein X is a halogen atom; R₄ is the formula:

wherein R₇ and R₈ are a hydrogen atom or, alternatively, they form abenzene nucleus together with adjacent carbon atoms, or the formula:

wherein Ar is a pyridyl group, quinolyl group or aryl group,

to obtain Compound (III) of the formula:

wherein A, R₂, R₃ and R₄ are as defined above,

(D) reacting Compound (III) with a compound of the formula:

wherein R₉ is a hydrogen atom, chlorine atom, linear or branched C₁₋₄alkyl group, C₁₋₃ alkoxy group, phenyl or benzyl group; R₁₀ and R₁₁,which may be the same or different, are a chlorine atom, linear orbranched C₁₋₄ alkyl group, C₁₋₃ alkoxy group, phenyl group or benzylgroup,

to obtain Compound (IV) of the formula:

wherein A, R₂, R₃ and R₄ are as defined above, and

(E) subjecting Compound (IV) to carbonylation at 9-position,carboxylation at 3-position, 11,12-cyclic carbamation and deprotectionof 2′-hydroxy group, to obtain Compound (V) of the formula:

wherein A and R₄ are as defined above.

MODE FOR CARRYING OUT THE INVENTION

The present invention is illustrated in more detail as follows.

In the present invention, the term “C₁₋₇ alkyl group” refers to linearor branched alkyl groups, which include methyl group, ethyl group,propyl group, isopropyl group, butyl group, t-butyl group, pentyl group,hexyl group and heptyl group. The term “C₁₋₃ alkoxy group” refers tomethoxy, ethoxy and propoxy groups. The term “halogen atom” refers tofluorine, chlorine, bromine, iodine atom and the like.

The present invention relates to a process for preparing Compound (V)from erythromycin A as a starting material, for example, according tothe following reaction scheme, and to intermediates thereof.

wherein A and R₁ through R₄ are as defined above, and more particularly,A is CH═CH or C≡C, R₁ is hydrogen atom, an acetyl group, a propionylgroup, a benzoyl group, a trimethylsilyl group or a triethylsilyl group,R₂ is hydrogen atom, an acetyl group, a propionyl group, a benzoylgroup, a trimethylsilyl group, a triethylsilyl group or at-butyldimethylsilyl group, R₃ is hydrogen atom, an acetyl group, apropionyl group, a benzoyl group, a trimethylsilyl group or atriethylsilyl group, and R₄ is a pyridyl group, a quinolyl group, apyridylthienyl group or a pyridylimidazolyl group.

Step 1. Compound (I) can be prepared according to a method described inWO9813373. That is, erythromycin A is reacted with ethylene carbonate inthe presence of a base in an inert solvent to give an erythromycin A11,12-cyclic carbonate compound. Here, the inert solvent includesdiethyl ether, ethyl acetate, dichloromethane, chloroform, acetone,N,N-dimethylformamide, toluene, tetrahydrofuran and a mixture thereof.The base includes sodium carbonate, potassium carbonate, cesiumcarbonate and pyridine. Next, the carbonyl group at the 9-position isreduced into a hydroxyl group by a reducing agent in an organic solvent,thereby 9-deoxo-9-hydroxyerythromycin A 11,12-cyclic carbonate can beobtained. The organic solvent used herein includes methanol, ethanol,isopropanol, propanol, tetrahydrofuran and N,N-dimethylformamide. Thereducing agent includes lithium borohydride, potassium borohydride,sodium cyanoborohydride and sodium borohydride. The hydroxyl group atthe 2′-position is then protected with an acetyl, propionyl, benzoyl,trimethylsilyl, triethylsilyl, t-butyldimethylsilyl group or the like toobtain Compound (I). In order to accelerate the reaction, a base can beadded for the acylation, and a salt with an acid can be added for thesilylation. Examples of the base to be used areN,N-dimethylaminopyridine, pyridine, triethylamine, imidazole, sodiumbicarbonate and potassium carbonate. Examples of the salt with an acidto be used are pyridine hydrochloride and ammonium chloride.

Step 2. Compound (I) obtained in Step 1 can be heated together with acompound of the formula:

wherein R₅ and R₆ are as defined above, in an inert solvent in thepresence of an acidic catalyst to obtain a decladinosylated 6,9-cyclicacetal compound (II). Here, the inert solvent includes dichloromethane,chloroform, dichloroethane, chlorobenzene, dichlorobenzene, toluene,xylene, etc. The acidic catalyst to be used includes pyridiniump-toluenesulfonate, pyridine hydrochloride, 3-pyridinesulfonic acid,trimethylamine hydrochloride, triethylamine hydrochloride, etc, and ispreferably, pyridinium p-toluenesulfonate. Examples of the compound offormula (1) to be used are acrolein dimethyl acetal, acrolein diethylacetal, acrolein di-n-propyl acetal, acrolein diisopropyl acetal,acrolein di-n-butyl acetal, acrolein diisobutyl acetal, propiolaldehydedimethyl acetal, propiolaldehyde diethyl acetal, propiolaldehydedi-n-propyl acetal, propiolaldehyde diisopropyl acetal, propiolaldehydedi-n-butyl acetal, propiolaldehyde diisobutyl acetal, etc.

Step 3. Compound (II) obtained in Step 2 can be reacted with a compoundof the formula:

in which R₇, R₈ and X are as defined above, or a compound of theformula:

in which Ar and X are as defined above, in an inert solvent in thepresence of, for example, a palladium catalyst to obtain Compound (III).In this case, copper iodide and phosphine may be optionally added. Theinert solvent includes toluene, tetrahydrofuran, dioxane,dimethoxyethane and N,N-dimethylformamide, and preferably toluene,tetrahydrofuran and N,N-dimethylformamide. The compound of formula (2)includes quinolyl chloride, pyridyl chloride, quinolyl bromide andpyridyl bromide and the compound of formula (3) includes pyridylthienylchloride and pyridylthienyl bromide, and of these compounds, quinolylbromide, pyridyl bromide and pyridylthienyl bromide are preferable.

Step 4. Compound (III) can be reacted with a compound of the formula:

wherein R₉, R₁₀ and R₁₁ are as defined above, in an organic solvent inthe presence of an activating agent such as a Lewis acid to obtainCompound (IV). Here, the organic solvent includes nitrobenzene,nitrotoluene, trichlorotoluene, benzonitrile and methylbenzoate, andpreferably nitrobenzene and nitrotoluene. Here, the compound of formula(6) includes trimethylsilane, triethylsilane, trichlorosilane,phenyldimethylsilane, diphenylsilane, triphenylsilane, triethoxysilane,diethylsilane and t-butyldimethylsilane, and preferably triethylsilaneand t-butyldimethylsilane. The activating agent to be used includes aLewis acid (e.g., titanium tetrachloride, aluminum chloride, zirconiumtetrachloride, tin tetrachloride, ferric trichloride, zinc chloride andtrifluoroboran etherate), trifluoromethane sulfonate and Nafion(registered trademark), and preferably titanium tetrachloride.

Step 5. Compound (IV) wherein R₃ is a hydrogen atom can be subjected toa reaction using a sulfur compound such as dimethyl sulfoxide (DMSO) anddimethyl sulfide (Me₂S) and an activating agent such as acetic anhydride(Ac₂O), N-chlorosuccinimide (NCS) or oxalyl chloride, whereby thehydroxy groups at the 3- and 9-positions are simultaneously oxidized toform a 3,9-dioxo compound, which is then led to 12-O-imidazolyl carbonylcompound using N,N′-carbonyldiimidazole and a base. Subsequently,ammonolysis using ammonia gas and intramolecular Michael additionreaction can lead to a 11,12-cyclic carbamate compound to obtainCompound (V). In this case, a base can also be added in order toaccelerate the intramolecular Michael addition reaction. Here, the baseincludes DBU, DBN, LiH, NaH, KH, NaHMDS, Cs₂CO₃, K₂CO₃, imidazole,KO-t-Bu or a mixture thereof. Compound (IV) wherein R₃ is protected issubjected to oxidation at the 9-position in the same manner as in theabove oxidation step, 11,12-cyclic carbamation, deprotection of thehydroxyl group at the 3-position, and then oxidation at the deprotected3-position in the same manner as described above to obtain Compound (V).

EXAMPLES Example 1 Preparation of Erythromycin A 11,12-cyclic Carbonate

To a solution of 150 g (0.20 mol) of erythromycin A in 0.5 L of toluenewere added 75 g (0.54 mol) of potassium carbonate and 75 g (0.85 mol) ofethylene carbonate, and the resulting solution was stirred at 40° C. for6 days. The solution was cooled, then to the reaction solution wereadded 0.2 L of toluene and 0.8 L of water, and the resulting solutionwas extracted. Then, the toluene layer was washed with a saturatedaqueous sodium chloride solution and dried over anhydrous magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theresulting residue was crystallized from ether to obtain 38.0 g of thetitle compound.

Example 2 Preparation of 9-deoxo-9-hydroxyerythromycin A 11,12-cyclicCarbonate

To a solution of 243 g (0.32 mol) of the compound obtained in Example 1in 1 L of methanol was added 32.0 g of sodium borohydride under icecooling. After 1 and 2 hours, sodium borohydride was further addedthereto in portions of 30.0 g and 23.0 g, respectively. The resultingsolution was stirred for 80 minutes, then the ice-bath was removed, and500 mL of methanol and 17.3 g of sodium borohydride were added thereto(the total volume of sodium borohydride was 2.7 mol). The resultingsolution was stirred for 40 minutes, then 4.5 L of ice water was addedthereto, and the precipitate was collected by filtration. Theprecipitate was dissolved in 2.5 L of chloroform, and washed with asaturated aqueous sodium chloride solution. The washed solution wasdried over anhydrous magnesium sulfate, and the solvent was evaporatedunder reduced pressure to obtain 232 g of the title compound.

Example 3 Preparation of 2′-O-acetyl-9-deoxo-9-hydroxyerythromycin A11,12-cyclic Carbonate

To a solution of 232 g (0.30 mol) of the compound obtained in Example 2in 1.2 L of chloroform was added 34.1 g (0.33 mol) of acetic anhydrideat room temperature. After having been stirred for 2 hours, the reactionsolution was washed with a saturated aqueous sodium bicarbonate solutionand water. Drying the organic layer over anhydrous magnesium sulfate andevaporating the solvent therefrom under reduced pressure gave 239 g ofthe title compound.

¹H NMR (500 MHz, CDCl₃) δ (ppm): 3.35 (s, 3H, 3″-O—CH₃), 3.39 (br, 1H,9-H), 4.22 (dd, 1H, J=2.1, 5.8 Hz, 3-H), 4.61 (d, 1H, J=7.3 Hz, 1′-H),4.80 (dd, 1H, J=7.6, 10.7 Hz, 2′-H)

ESI-MS: m/z=804.3 [M+H]⁺

Example 4 Preparation of2′-O-acetyl-6,9-O-acrylidene-9-deoxo-9-hydroxy-5-O-desosaminylerythronolide A 11,12-cyclic Carbonate

To a solution of 79.6 g (0.099 mol) of the compound obtained in Example3 in 400 mL of toluene were added 53.8 g (0.41 mol) of acroleine diethylacetal and 29.9 g (0.12 mol) of pyridinium p-toluenesulfonate. Theresulting solution was refluxed with heating for 5 hours, and allowed tostand at room temperature overnight. The precipitate was collected byfiltration and washed with 100 mL of toluene. The precipitate was addedin a mixture of 500 mL of chloroform and 100 mL of a saturated aqueoussodium bicarbonate solution and dissolved while stirring. The chloroformlayer was collected by separation, washed with a saturated aqueoussodium bicarbonate solution and water, and dried over anhydrousmagnesium sulfate. Evaporation of the solvent therefrom under reducedpressure gave 54.2 g of the title compound.

¹H NMR (500 MHz, CDCl₃) δ (ppm): 3.80 (dd, 1H, J=4.0, 5.8 Hz, 9-H), 4.60(d, 1H, J=7.3 Hz, 1′-H), 4.77 (dd, 1H, J=7.6, 10.7 Hz, 2′-H), 5.43 (d,1H, J=5.5 Hz, >CH—CH═CH₂), 5.80 (ddd, 1H, J=4.9, 10.4, 17.1 Hz,>CH—CH═CH₂)

¹³C NMR (125 MHz, CDCl₃) δ (ppm): 76.9 (3-C), 78.7 (6-C), 82.5 (9-C),92.2 (>CH—CH═CH₂), 99.8 (1′-C), 115.8 (>CH—CH═CH₂)

ESI-MS: m/z=684.2 [M+H]⁺

Example 5 Preparation of6,9-O-acrylidene-9-deoxo-2′,3-di-O-acetyl-9-hydroxy-5-O-desosaminylerythronolide A 11,12-cyclic Carbonate

To a solution of 54.2 g (0.079 mol) of the compound obtained in Example4 in 271 mL of chloroform were added 16.1 g (0.16 mol) of triethylamineand 9.69 g (0.079 mol) of dimethylaminopyridine. Then 16.2 g (0.16 mol)of acetic anhydride was added to the resulting solution at roomtemperature, which was then stirred overnight. 8.12 g (0.08 mol) ofacetic anhydride and 8.05 g (0.08 mol) of triethylamine were furtheradded thereto and the resulting solution was stirred for 4.5 hours, andthen washed with a saturated aqueous ammonium chloride solution, asaturated aqueous sodium bicarbonate solution and a saturated aqueoussodium chloride solution. The organic layer was dried over anhydrousmagnesium sulfate, then the solvent was evaporated therefrom underreduced pressure. The concentrated residue was purified by a silica gelcolumn chromatography (eluent; acetone:hexane:triethylamine=2:10:0.2),dissolved in 300 mL of toluene and washed with a saturated aqueousammonium chloride solution, a saturated aqueous sodium bicarbonatesolution and a saturated aqueous sodium chloride solution. The resultingsolution was dried over anhydrous magnesium sulfate, then the solventwas evaporated under reduced pressure to obtain 35.2 g of the titlecompound.

¹H NMR (500 MHz, CDCl₃) δ (ppm): 2.08 (s, 3H, 2′-OAc), 2.15 (s, 3H,3-OAc), 3.81 (dd, 1H, J=3.9, 6.0 Hz, 9-H), 4.18 (d, 1H, J=7.6 Hz, 1′-H),5.43 (d, 1H, J=4.6 Hz, >CH—CH═CH₂), 5.83 (ddd, 1H, J=4.2, 10.3, 17.0 Hz,>CH—CH═CH₂)

¹³C NMR (125 MHz, CDCl₃) δ (ppm): 77.7 (3-C), 78.5 (6-C), 82.4 (9-C),91.9 (>CH—CH═CH₂), 100.4 (1′-C), 116.0 (>CH—CH═CH₂), 169.9 (3-OCO—CH₃)

ESI-MS: m/z=726.2 [M+H]⁺

Example 6 Preparation of9-deoxo-2′,3-di-O-acetyl-9-hydroxy-6,9-O-(3-(3-quinolyl)acrylidene)-5-O-desosaminylerythronolide A 11,12-cyclic Carbonate

To a solution of 14.5 g (0.020 mol) of the compound obtained in Example5 in 145 mL of tetrahydrofuran were added 6.24 g (0.030 mol) of3-bromoquinoline, 9.67 g (0.030 mol) of tetrabutylammonium bromide and7.76 g (0.060 mol) of diisopropylethylamine. After addition of 0.449 g(0.002 mol) of palladium acetate, the resulting solution was refluxedwith heating under a nitrogen atmosphere for 7 hours. The solution wasallowed to stand at room temperature overnight, then 0.449 g (0.002 mol)of palladium acetate was further added, and the resulting solution wasrefluxed with heating for 4 hours. The solution was allowed to stand forcooling, then the cooled solution was diluted with 500 mL of chloroform,washed with a saturated aqueous sodium bicarbonate solution and asaturated aqueous sodium chloride solution. The organic layer was driedover anhydrous magnesium sulfate, then the solvent was evaporated underreduced pressure. The concentrated residue was purified by a silica gelcolumn chromatography (eluent;acetone:hexane:triethylamine=2:10:0.2−5:10:0.2) to obtain 14.1 g of thetitle compound.

¹H NMR (500 MHz, CDCl₃) δ (ppm): 3.88 (dd, J=3.7, 6.1 Hz, 1H, 9-H), 4.21(d, 1H, J=7.3 Hz, 1′-H), 5.70 (d, 1H, J=4.3 Hz, >CH—CH═CH—), 6.90 (d,1H, J=16.5 Hz, ═CH-quinolyl), 9.08 (d, 1H, J=2.4 Hz, 2-H of quinoline)

¹³C NMR (125 MHz, CDCl₃) δ (ppm): 78.9 (6-C), 82.8 (9-C), 91.4(>CH—CH═CH—), 100.5 (1′-C), 128.1 (═CH-quinolyl), 129.8 (3-C ofquinoline)

ESI-MS: m/z=853.1 [M+H]⁺

Example 7 Preparation of9-deoxo-2′,3-di-O-acetyl-9-hydroxy-6-O-((3-quinol-3-yl)prop-2-enyl)-5-O-desosaminylerythronolide A 11,12-cyclic Carbonate

To a solution of 2.56 g (3.0 mmol) of the compound obtained in Example 6in 26 mL of nitrobenzene was added 1.05 g (9.0 mmol) of triethylsilane.Under nitrogen atmosphere, 2.0 mL (0.018 mol) of titanium tetrachloridewas added thereto under ice-cooling. After 1.5 hours, the reactionsolution was added to a mixture of 270 mL of chloroform and 200 mL of 5mol/L aqueous sodium hydroxide solution while stirring. The precipitatewas removed by filtration, and the organic layer was separated andwashed with a saturated aqueous sodium chloride solution. The organiclayer was dried over anhydrous magnesium sulfate, then the solvent wasevaporated under reduced pressure. The concentrated residue was purifiedby a silica gel column chromatography (eluent;acetone:hexane:triethylamine=2:10:0.2−10:10:0.2) to obtain 1.89 g of thetitle compound.

¹H NMR (500 MHz, CDCl₃) δ (ppm): 0.99 (d, 3H, J=6.7 Hz, 8-CH₃),3.30-3.42 (m, 2H, 5′-, 9-H), 4.13 (d, 1H, J=7.3 Hz, 1′-H), 4.24 (dd, 1H,J=7.3, 11.6 Hz, 6-OCH ₂CH═CH—), 4.34 (dd, 1H, J=6.11, 11.6 Hz, 6-OCH₂CH═CH—), 9.08 (d, 1H, J=1.8 Hz, 2-H of quinoline)

¹³C NMR (125 MHz, CDCl₃) δ (ppm): 64.6 (6-OCH₂CH═CH—), 79.3 (9-C), 80.3(6-C), 100.8 (1′-C), 129.9 (3-C of quinoline), 131.0 (═CH-quinolyl)

ESI-MS: m/z=853.2 [M−H]⁻

Example 8 Preparation of2′,3-di-O-acetyl-6-O-((3-quinol-3-yl)prop-2-enyl)-5-O-desosaminylerythronolide A 11,12-cyclic Carbonate

To a solution of 1.71 g (2.0 mmol) of the compound obtained in Example 7in 15.6 g (0.20 mol) of dimethyl sulfoxide was added 10.2 g (0.10 mol)of acetic anhydride at room temperature, followed by stirring for 6.5hours. The reaction solution was soaked in an ice-bath, 100 mL of 5%aqueous ammonia was added. The precipitate was extracted withchloroform, and the extract was washed with a saturated aqueous sodiumchloride solution. The organic layer was dried over anhydrous magnesiumsulfate, then the solvent was evaporated under reduced pressure, and theconcentrated residue was purified by a silica gel column chromatography(eluent; acetone:hexane:triethylamine=8:10:0.2) to obtain 1.65 g of thetitle compound.

¹H NMR (500 MHz, CDCl₃) δ (ppm): 1.14 (d, 3H, J=7.0 Hz, 8-CH₃), 3.01 (q,1H, J=7.1 Hz, 10-H), 3.99 (dd, 1H, J=7.0, 11.3 Hz, 6-OCH ₂CH═CH—),4.04-4.12 (m, 2H, 6-OCH ₂CH═CH—, 1′-H), 9.03 (d, 1H, J=2.2 Hz, 2-H ofquinoline)

ESI-MS: m/z=853.1 [M+H]⁺

Example 9 Preparation of2′,3-di-O-acetyl-10,11-anhydro-6-O-((3-quinol-3-yl)prop-2-enyl)-5-O-desosaminylerythronolide A

To a solution of 1.63 g (1.9 mmol) of the compound obtained in-Example 8in 5 mL of dimethylformamide was added 0.66 g (5.7 mmol) oftetramethyguanidine. The resulting solution was stirred at 100° C. for 2hours and diluted with 200 mL of chloroform. The diluted solution waswashed with a saturated aqueous sodium chloride solution, dried overanhydrous magnesium sulfate, then the solvent was evaporated underreduced pressure. The concentrated residue was purified by a silica gelcolumn chromatography (eluent; acetone:hexane:triethylamine=6:10:0.2) toobtain 1.55 g of the title compound.

ESI-MS: m/z 809.1[M+H]⁺

Example 10 Preparation of2′,3-di-O-acetyl-6-O-((3-quinol-3-yl)prop-2-enyl)-5-O-desosaminylerythronolide A 11,12-cyclic Carbamate

To a solution of 1.55 g (1.9 mmol) of the compound obtained in Example 9in 8 mL of dimethylformamide was added 20 mL of tetrahydrofuran. To theresulting solution were added 1.24 g (7.6 mmol) ofN,N-carbonyldiimidazole and 0.41 g (2.7 mmol) of1,8-diazabicyclo[5.4.0]-7-undecene. The solution was allowed to stand atroom temperature overnight, then ammonia gas was introduced therein at0° C. for 4 hours then at 20° C. for 2 hours. Then 0.24 g (2.1 mmol) ofpotassium t-butoxide was added, and the resulting solution was stirredat room temperature overnight. 1 Mol/L hydrochloric acid was added tothe solution to adjust to pH 6, then the resulting solution wasextracted with isopropyl acetate and chloroform. The organic layer waswashed with a saturated aqueous ammonium chloride solution, a saturatedaqueous sodium bicarbonate solution and a saturated aqueous sodiumchloride solution, in this order, and dried over anhydrous magnesiumsulfate, and the solvent was evaporated under reduced pressure to obtain1.46 g of the title compound.

ESI-MS: m/z=852.3[M+H]⁺

Example 11 Preparation of6-O-((3-quinol-3-yl)prop-2-enyl)-5-O-desosaminyl erythronolide A11,12-cyclic Carbamate

To a solution of 0.73 g (0.86 mmol) of the compound obtained in Example10 in 10 mL of methanol was added 0.65 g (4.3 mmol) of1,8-diazabicyclo[5.4.0]-7-undecene, and the resulting solution wasrefluxed with heating for 5 hours. The solvent was evaporated underreduced pressure, then the concentrated residue was dissolved inchloroform, and washed with a saturated aqueous ammonium chloridesolution, a saturated aqueous sodium bicarbonate solution and asaturated aqueous sodium chloride solution, in this order. The organiclayer was dried over anhydrous magnesium sulfate, then the solvent wasevaporated under reduced pressure to obtain 0.58 g of the titlecompound.

ESI-MS: m/z=768.4[M+H]⁺

Example 12 Preparation of2′-O-propionyl-6-O-((3-quinol-3-yl)prop-2-enyl)-5-O-desosaminylerythronolide A 11,12-cyclic Carbamate

To a solution of 0.56 g (0.73 mmol) of the compound obtained in Example11 in 11 mL of chloroform was added 0.12 g (0.88 mmol) of propionicanhydride, and the resulting solution was stirred at room temperaturefor 2 hours. 0.12 g (0.88 mmol) of propionic anhydride was further addedthereto, and the resulting solution was stirred for additional an hour.The reaction solution was diluted with 100 mL of chloroform, and washedwith a saturated aqueous sodium bicarbonate solution and a saturatedaqueous sodium chloride solution, in this order. The organic layer wasdried over anhydrous magnesium sulfate, then the solvent was evaporatedunder reduced pressure. The concentrated residue was purified by asilica gel column chromatography (eluent;acetone:hexane:triethylamine=2:10:0.2−6:10:0.2) to obtain 0.45 g of thetitle compound.

ESI-MS: m/z=824.3[M+H]⁺

Example 13 Preparation of3-deoxy-3-oxo-2′-O-propionyl-6-O-((3-quinol-3-yl)prop-2-enyl)-5-O-desosaminylerythronolide A 11,12-cyclic Carbamate

To 1 mL of a dichloromethane solution of 83 mg of NCS and 54 μL of Me₂Swas added dropwise at −10° C. 2 mL of a dichloromethane solution of 0.3g of the compound obtained in Example 12, and the resulting solution wasstirred for 45 minutes. To the reaction solution was added 0.12 mL of asolution of triethylamine in 0.5 mL of dichloromethane, and stirring wascontinued at −10° C. for further 3 hours. After working up in a similarmanner to Example 6, purification of the concentrated residue by asilica gel column chromatography (eluent; chloroform: methanol:aqueousammonia=20:1:0.1) gave 0.28 g of the title compound.

ESI-MS: m/z=844.4[M+Na]⁺

Example 14 Preparation of3-deoxy-3-oxo-6-O-((3-quinol-3-yl)prop-2-enyl)-5-O-desosaminylerythronolide A 11,12-cyclic Carbamate

A solution of 0.2 g of the compound obtained in Example 13 in 5 mL ofmethanol was refluxed with heating for 2 hours. The methanol wasevaporated under reduced pressure, and the residue was purified by asilica gel column chromatography (eluent; chloroform:methanol:aqueousammonia=20:1:0.1) to give 0.16 g of the title compound, (the compound ofExample 104 of U.S. Pat. No. 5,866,549).

ESI-MS: m/z=788.5[M+Na]⁺

Example 15 Preparation of2′-O-acetyl-9-deoxo-9-hydroxy-6,9-O-(3-(3-quinolyl)acrylidene)-5-O-desosaminylerythronolide A 11,12-cyclic Carbonate

To a solution of 54.6 g (0.080 mol) of the compound obtained in Example4 in 273 mL of tetrahydrofuran were added 18.3 g (0.088 mol) of3-bromoquinoline, 28.3 g (0.088 mol) of tetrabutylammonium bromide and20.6 g (0.16 mol) of diisopropylethylamine. 1.79 g (8.0 mmol) ofpalladium acetate was added to the solution, which was then refluxedwith heating for 8 hours. The solution was allowed to stand for cooling,then almost all of the solvent was evaporated under reduced pressure,and the residue was dissolved in 546 mL of chloroform and washed with200 mL of 2 mol/L aqueous sodium hydroxide solution. The formed solidwas removed off by filtration, and the organic layer was washed with asaturated aqueous sodium chloride solution and dried over anhydrousmagnesium sulfate. Then the solvent was evaporated under reducedpressure, and the concentrated residue was purified by a silica gelcolumn chromatography (eluent;acetone:hexane:triethylamine=3:10:0.2−6:10:0.2) to obtain 55.9 g of thetitle compound.

¹H NMR (500 MHz, CDCl₃) δ (ppm): 3.20-3.28 (m, 1H, 5′-H), 3.80-3.90 (m,2H, 5-H & 9-H), 5.68 (d, 1H, J=4.3 Hz, >CH—CH═CH—), 6.76 (d, 1H, J=15.9Hz, ═CH-quinolyl), 8.97 (d, 1H, J=1.8 Hz, 2-H of quinoline)

¹³C NMR (125 MHz, CDCl₃) δ (ppm): 76.0 (3-C), 79.0 (6-C), 82.7 (9-C),90.9 (>CH—CH═CH—), 99.7 (1′-C), 127.5 (═CH-quinolyl), 129.8 (3-C ofquinoline) ESI-MS: m/z=811.3 [M+H]+

Example 16 Preparation of2′-O-acetyl-9-deoxo-9-hydroxy-6-O-((3-quinol-3-yl)prop-2-enyl)-5-O-desosaminylerythronolide A 11,12-cyclic Carbonate

To a solution of 45.7 g (0.056 mol) of the compound obtained in Example15 in 457 mL of nitrobenzene was added 19.7 g (0.17 mol) oftriethylsilane. Under nitrogen atmosphere, 37 mL (0.34 mol) of titaniumtetrachloride was added to the solution dropwise under ice-cooling over10 minutes. The resulting solution was stirred on an ice-bath for 10minutes, then the ice-bath was removed, and the solution was stirred foradditional 3 hours. Under ice-cooling, 500 mL of 2 mol/L aqueous sodiumhydroxide solution was added to the solution. 1000 mL of chloroform wasadded thereto, stirring was continued for 30 minutes, and the solid wasremoved off by filtration. The organic layer was washed with a saturatedaqueous sodium chloride solution and dried over anhydrous magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theconcentrated residue was purified by a silica gel column chromatography(eluent; acetone:hexane:triethylamine=2.5:10:0.2−6:10:0.2) to obtain33.3 g of the title compound.

¹H NMR (500 MHz, CDCl₃) (ppm): 1.92-2.03 (m, 2H, 4-H & 10-H), 3.28-3.38(m, 2H, 9-H & 5′-H), 4.04-4.20 (m, 3H, 3-OH & —O—CH ₂-vinyl), 6.73 (d,1H, J=15.8 Hz, ═CH-quinolyl), 9.02 (d, 1H, J=2.1 Hz, 2-H of quinoline)

¹³C NMR (125 MHz, CDCl₃) δ (ppm): 63.6 (6-OCH₂CH═CH—), 76.6 (3-C), 79.6(9-C), 80.6 (6-C), 100.0 (1′-C), 129.5 (3-C of quinoline), 130.4(═CH-quinolyl)

ESI-MS: m/z=813.3 [M+H]⁺

Example 17 Preparation of2′-O-acetyl-3-deoxy-3-oxo-6-O-((3-quinol-3-yl)prop-2-enyl)-5-O-desosaminylerythronolide A 11,12-cyclic Carbonate

To a solution of 1.63 g (2.0 mmol) of the compound obtained in Example16 in 15.6 g (0.20 mol) of dimethyl sulfoxide was added 10.2 g (0.10mol) of acetic anhydride at room temperature. The resulting solution wasallowed to stand at room temperature overnight, and ice-cooled, then 100mL of 5% aqueous ammonia was added thereto. The resulting solution wasextracted with 200 mL of chloroform, and the extract was washed with asaturated aqueous sodium chloride solution. The organic layer was driedover anhydrous magnesium sulfate, then the solvent was evaporated underreduced pressure. The concentrated residue was purified by a silica gelcolumn chromatography (eluent; acetone:hexane:triethylamine=4:10:0.2) toobtain 1.13 g of the title compound.

¹H NMR (500 MHz, CDCl₃) δ (ppm): 3.00 (q, 1H, J=6.7 Hz, 10-H), 3.18 (dq,1H, J=4.9, 7.9 Hz, 4-H), 3.52-3.60 (m, 1H, 5′-H), 3.69 (dd, 1H, J=7.6,11.3 Hz, 6-O—CH ₂—), 3.86-3.92 (m, 2H, 2-H & 6-O—CH ₂—), 6.58 (d, 1H,J=15.9 Hz, ═CH-quinolyl), 9.01 (d, 1H, J=2.5 Hz, 2-H of quinoline)

ESI-MS: m/z=809.2 [M+H]⁺

Example 18 Preparation of2′-O-acetyl-3-deoxy-3-oxo-6-O-((3-quinol-3-yl)prop-2-enyl)-5-O-desosaminylerythronolide A 11,12-cyclic Carbamate

To a solution of 0.809 g (1.0 mmol) of the compound obtained in Example17 in 16 mL of tetrahydrofuran was added 0.350 g (2.3 mmol) of1,8-diazabicyclo[5.4.0]-7-undecene, and the resulting solution wasallowed to stand at room temperature for 4 days. 0.649 g (4.0 mmol) ofcarbonyl diimidazole was added to the solution, which was then stirredat room temperature for 70 minutes. The solution was then cooled in anice-bath, and ammonia gas was introduced thereinto for 8 hours. Theresulting solution was allowed to stand at room temperature overnight,then cooled in an ice-bath, and ammonia gas was introduced thereinto for6.5 hours. The resulting solution was allowed to stand at roomtemperature overnight, then the reaction solution was diluted with 200mL of toluene, washed with a saturated aqueous sodium chloride solution,and dried over anhydrous magnesium sulfate. The solvent was evaporatedunder reduced pressure. The concentrated residue was purified by asilica gel column chromatography (eluent; chloroform:methanol: 28%aqueous ammonia=20:1:0.1) to obtain 0.405 g of the title compound.

ESI-MS: m/z=806.3[M−H]⁻

Example 19 Preparation of3-deoxy-3-oxo-6-O-((3-quinol-3-yl)prop-2-enyl)-5-O-desosaminylerythronolide A 11,12-cyclic Carbamate

A solution of 0.190 g (0.235 mmol) of the compound obtained in Example18 in 4.8 mL of methanol was refluxed with heating for 3 hours. Thesolvent was evaporated under reduced pressure, then 2 mL of hexane wasadded, and the precipitated crystals were collected by filtration toobtain 0.148 g of the title compound.

Example 20 Preparation of2′-O-acetyl-3-deoxy-3-oxo-6-O-((3-quinol-3-yl)prop-2-enyl)-5-O-desosaminylerythronolide A 11,12-cyclic Carbonate

7.5 mL of a cooled (−18° C.) methylene chloride solution of 0.93 g (15mmol) of dimethyl sulfide was added dropwise to 15 mL of a cooled (−18°C.) methylene chloride suspension of 1.60 g (12 mmol) ofN-chlorosuccinimide, and the resulting mixture was stirred at −18° C.for 30 minutes. To the reaction solution was added dropwise −18° C. 15mL of a methylene chloride solution of 2.44 g (3.0 mmol) of the compoundobtained in Example 16, and the resulting solution was stirred for anhour. Next, 7.5 mL of a methylene chloride solution of 1.52 g (15 mmol)of triethylamine was added thereto dropwise at −18° C., while stirringwas continued for additional 2 hours. To the reaction solution was added50 g of ice, the resulting solution was extracted with 150 mL ofchloroform, the extract was washed with a saturated aqueous sodiumbicarbonate solution and a saturated aqueous sodium chloride solution.The extract was dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the concentrated residue waspurified by a silica gel column chromatography (eluent;acetone:hexane:triethylamine=4:10:0.2) to obtain 1.89 g of the titlecompound.

Example 21 Preparation of 2′-O-benzoyl-9-deoxo-9-hydroxyerythromycin A11,12-cyclic Carbonate

1.00 g (1.31 mmol) of the compound obtained in Example 2 was dissolvedin 50 mL of toluene and the solvent was evaporated under reducedpressure. The resulting residue was dissolved in 5 mL oftetrahydrofuran, and thereto were added 594 mg (2.63 mmol) of benzoicanhydride and 199 mg (1.97 mmol) of triethylamine. The resulting mixturewas stirred at room temperature for 16 hours, 20 mL of ethyl acetate and10 mL of purified water were added, and the mixture was stirred at roomtemperature for 10 minutes. After separating the mixture into layers,the aqueous layer was twice extracted with 20 mL portions of ethylacetate. The combined organic layer was washed with 10% aqueouspotassium dihydrogen phosphate solution, 10% aqueous sodium carbonatesolution and saturated aqueous sodium chloride solution, dried overanhydrous magnesium sulfate, and filtered. The solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (eluent; acetone:hexane:triethylamine=2:10:0.2−5:10:0.2)to obtain 1.03 g of the title compound.

¹H NMR (500 MHz, CDCl₃) δ (ppm): 5.08(dd, 1H, J=10.4, 7.3 Hz, 2′-H),7.43(t, 2H, J=7.6 Hz, aromatic proton), 7.55 (t, 1H, J=7.3 Hz, aromaticproton), 7.99-8.05(m, 2H, aromatic proton)

¹³C NMR(125 MHz, CDCl₃) δ (ppm): 128.2(aromatic carbon of benzoylgroup), 129.7(aromatic carbon of benzoyl group), 130.7(aromatic carbonof benzoyl group), 132.6 (aromatic carbon of benzoyl group), 165.3(2′-O—CO—)

ESI-MS: m/z=888.5[M+Na]⁺

Example 22 Preparation of6,9-O-acrylidene-2′-O-benzoyl-9-deoxo-9-hydroxy-5-O-desosaminylerythronolide A 11,12-cyclic Carbonate

10.0 g (11.5 mmol) of the compound obtained in Example 21 was dissolvedin 150 mL of toluene and the solvent was evaporated under reducedpressure. The resulting residue was dissolved in 50 mL of toluene, andthereto were added 6.01 g (46.2 mmol) of acrolein diethyl acetal and3.48 g (13.8 mmol) of pyridinium p-toluenesulfonate. The resultingmixture was refluxed with heating for 4.5 hours, and then allowed tocool and left to stand.

To the reaction solution were added 150 mL of ethyl acetate and 200 mLof 4 mol/L saturated aqueous sodium hydrogen carbonate solution. Afterseparation into layers, the aqueous layer was twice extracted with 50 mLportions of ethyl acetate. The organic layers were combined, washed with50 mL of saturated aqueous sodium chloride solution and dried overanhydrous magnesium sulfate. Evaporation of the solvent under reducedpressure gave a crude product. Purification of the concentrated residueby silica gel column chromatography (eluent;acetone:hexane:triethylamine=2:10:0.2−4:10:0.2) gave 5.94 g of the titlecompound.

¹H NMR (500 MHz, CDCl₃) δ (ppm): 5.10(s, 1H, 11-H), 5.25(d, 1H, J=17.1Hz, >CH—CH═CH ₂), 5.41(d, 1H, J=4.9 Hz, >CH—CH═CH₂), 5.79(m, 1H,>CH—CH=CH₂)

¹³C NMR(125 MHz, CDCl₃) δ (ppm): 92.2(>CH—CH═CH₂), 115.8(>CH—CH═CH₂),136.3(>CH—CH═CH₂)

ESI-MS: m/z=768.4[M+Na]⁺

Example 23 Preparation of2′-O-benzoyl-9-deoxo-9-hydroxy-6,9-O-(3-(3-quinolyl)acrylidene)-5-O-desosaminylerythronolide A 11,12-cyclic Carbonate

5.60 g (7.51 mmol) of the compound obtained in Example 22 was reacted ina similar manner to Example 15 to obtain 5.10 g of the title compound.

¹H NMR (500 MHz, CDCl₃) δ (ppm): 5.66(d, 1H, J=4.9 Hz, >CH—CH═CH—),6.29(dd, 1H, J=15.9, 4.9 Hz, >CH—CH═CH-quinolyl), 6.72(d, 1H, J=15.9 Hz,═CH-quinolyl), 8.98(d, 1H, J=1.8 Hz, 2-H of quinoline)

¹³C NMR (125 MHZ, CDCl₃) δ (ppm): 79.0(6-C), 82.8(9-C),91.0(>CH—CH═CH—), 127.4(═CH-quinolyl), 129.9(>CH—CH═CH-quinolyl),149.4(2-C of quinoline)

ESI-MS: m/z=895.3[M+Na]⁺

Example 24 Preparation of2′-O-benzoyl-9-deoxo-9-hydroxy-6-O-((3-quinol-3-yl)prop-2-enyl)-5-O-desosaminylerythronolide A 11,12-cyclic Carbonate

1.49 g (1.71 mmol) of the compound obtained in Example 23 was reacted ina similar manner to Example 16 to obtain 790 mg of the title compound.

¹H NMR(500 MHz, CDCl₃) δ (ppm): 3.28(m, 1H, 9-H), 4.07-4.18(m, 2H,6-O—CH ₂CH═CH—), 6.50(m, 1H, 6-O—CH₂CH═CH—), 6.71(d, 1H, J=16.1 Hz,═CH-quinolyl), 9.00(d, 1H, J=2.2 Hz, 2-H of quinoline)

¹³C NMR(125 MHz, CDCl₃) δ (ppm): 63.6 (6-O—CH₂CH═CH—), 79.7(9-C),80.7(6-C), 127.4(6-O—CH₂ CH═CH—), 130.3(═CH-quinolyl), 149.4(2-C ofquinoline) ESI-MS: m/z=897.4[M+Na]⁺

Example 25 Preparation of6,9-O-acrylidene-9-deoxo-9-hydroxy-5-O-desosaminyl erythronolide A11,12-cyclic Carbonate

3.00 g (3.94 mmol) of the compound obtained in Example 2 was dissolvedin 100 mL of toluene and the solvent was evaporated under reducedpressure. The resulting concentrated residue was dissolved in 30 mL oftoluene, and thereto were added 2.05 g (15.7 mmol) of acrolein diethylacetal and 1.19 g (4.74 mmol) of pyridinium p-toluenesulfonate. Themixture was refluxed with heating for one hour and 50 minutes, allowedto cool, and left to stand. 50 mL of ethyl acetate and 30 mL of 4 mol/Laqueous sodium hydroxide solution were added thereto. The resultingmixture was stirred at room temperature for 30 minutes and separatedinto layers, and the aqueous layer was twice extracted with 20 mLportions of ethyl acetate. The organic layers were combined, washed withsaturated aqueous sodium chloride solution and dried over anhydrousmagnesium sulfate. Evaporation of the solvent under reduced pressuregave a crude product. The concentrated residue was purified by silicagel column chromatography (eluent; chloroform:methanol:aqueousammonia=30:1:0.1−10:1:0.1) to obtain 1.50 g of the title compound.

¹H NMR(500 MHz, CDCl₃) δ (ppm): 5.14 (d, 1H, J=10.4 Hz, >CH—CH═CH ₂),5.15(s, 1H, 11-H), 5.28(d, 1H, J=17.1 Hz, >CH—CH═CH ₁₂), 5.45(d, 1H,J=4.9 Hz, >CH—CH═CH₂), 5.81(ddd, 1H, J=4.9, 10.4, 17.1 Hz, >CH—CH═CH₂)

¹³C NMR(125 MHz, CDCl₃) δ (ppm): 78.6(6-C), 82.7(9-C), 91.8(>CH—CH═CH₂),115.8(>CH—CH═CH₂), 136.2(>CH—CH═CH₂)

ESI-MS: m/z=642.3[M+H]⁺

Example 26 Preparation of9-deoxo-9-hydroxy-6-O-((3-quinol-3-yl)prop-2-enyl)-5-O-desosaminylerythronolide A 11,12-cyclic Carbonate

A solution of 93.5 g (0.115 mol) of the compound obtained in Example 16in 500 mL of methanol was refluxed with heating for 4 hours. Afterallowing the resulting solution to cool, the solvent was evaporatedunder reduced pressure. Recrystallization of the resulting residue fromethyl acetate gave 70.6 g of the title compound.

¹H NMR (500 MHz, CDCl₃) δ (ppm): 3.17(d, 1H, J=5.5 Hz, 9-H), 3.25(dd,1H, J=10.4, 7.3 Hz, 2′-H), 3.79(dd, 1H, J=9.8, 2.4 Hz, 3H), 9.01(d, 1H,J=1.8 Hz, 2-H of quinoline)

¹³C NMR(125 MHz, CDCl₃) δ (ppm): 70.5(2′-C), 77.9(3-C), 80.6(9-C),81.2(6-C)

ESI-MS: m/z=771.4[M+H]⁺

Example 27 Preparation of2′-O-benzoyl-9-deoxo-9-hydroxy-6-O-((3-quinol-3-yl)prop-2-enyl)-5-O-desosaminylerythronolide A 11,12-cyclic Carbonate

67.9 g (88.1 mmol) of the compound obtained in Example 26 was dissolvedin 500 mL of toluene and the solvent was evaporated under reducedpressure. The residue was dissolved in 135 mL of tetrahydrofuran, andthereto was added 20.9 g (92.4 mmol) of benzoic anhydride. Afterstirring the mixture at 40-44° C. for 5.5 hours, 2.00 g (8.84 mmol) ofbenzoic anhydride was additionally added, and the resulting mixture wasstirred with heating at the same temperature as above for 6 hours. Tothe reaction solution were added 34 mL of purified water and 13.0 g ofpotassium carbonate, and the resulting mixture was stirred with heatingat 40-44° C. for 2 hours. After allowing the mixture to cool, 200 mL ofethyl acetate and 100 mL of purified water were added. The resultingmixture was separated into layers, and the aqueous layer was twiceextracted with 100 mL portions of ethyl acetate. The organic layers werecombined, washed with 4 mol/L aqueous sodium hydroxide solution andsaturated aqueous sodium chloride solution, dried over anhydrousmagnesium sulfate, and filtered. Evaporation of the solvent underreduced pressure gave 79.0 g of the title compound (the same compound asthat obtained in Example 24).

Example 28 Preparation of2′-O-benzoyl-3-deoxy-3-oxo-6-O-((3-quinol-3-yl)prop-2-enyl)-5-O-desosaminylerythronolide A 11,12-cyclic Carbonate

78.8 g (90.0 mmol) of the compound obtained in Example 27 was reacted ina similar manner to Example 20 to obtain 71.7 g of the title compound.

¹H NMR(500 MHz, CDCl₃) δ (ppm): 2.72(m, 1H, 8-H), 3.06(m, 1H, 4-H),3.77(q, 1H, J=6.7 Hz, 2-H)

¹³C NMR(125 MHz, CDCl₃) δ (ppm): 168.6(1-C), 205.1(3-C), 212.4(9-C)

ESI-MS: m/z=893.3[M+Na]⁺

Example 29 Preparation of10,11-anhydro-2′-O-benzoyl-3,11-dideoxy-3-oxo-6-O-((3-quinol-3-yl)prop-2-enyl)-5-O-desosaminylerythronolide A

To a solution of 20.0 g (23.0 mmol) of the compound obtained in Example28 in 400 mL of tetrahydrofuran was added 15.9 g (0.115 mol) ofanhydrous potassium carbonate. The resulting mixture was refluxed withheating for 23 hours. After allowing the reaction mixture to cool, theprecipitate was filtered off and washed with 200 mL of ethyl acetate.The filtrate and washings thus obtained were washed with saturatedaqueous sodium chloride solution, dried over anhydrous magnesiumsulfate, and filtered. The solvent was evaporated under reducedpressure. Purification of the crude product thus obtained by silica gelcolumn chromatography (eluent;acetone:hexane:triethylamine=3:10:0.2−5:10:0.2) gave 19.8 g of the titlecompound.

¹H NMR(500 MHz, CDCl₃) δ (ppm): 2.03(s, 3H, 10-Me), 4.97(dd, 1H, J=10.3,2.6 Hz, 13-H), 5.07(dd, 1H, J=10.4, 7.6 Hz, 2′-H), 6.48(s, 1H, 11-H),8.89(d, 1H, J=2.1 Hz, 2-H of quinoline)

¹³C NMR(125 MHz, CDCl₃) δ (ppm): 73.5(12-C), 139.8(10-C), 141.1(11-C),208.3(3-C & 9-C)

ESI-MS: m/z=849.2[M+Na]⁺

Example 30 Preparation of10,11-anhydro-12-O-aminocarbonyl-2′-O-benzoyl-3,11-dideoxy-3-oxo-6-O-((3-quinol-3-yl)prop-2-enyl)-5-O-desosaminylerythronolide A

To a solution of 18.6 g (22.5 mmol) of the compound obtained in Example29 in 372 mL of tetrahydrofuran were added 10.9 g (67.2 mmol) ofcarbonyldiimidazole and 342 mg (2.25 mmol) of1,8-diazabicyclo[5.4.0]undec-7-ene. The resulting mixture was stirredfor 3 hours with cooling. Then, under ice-cooling, ammonia gas wasintroduced into the mixture for 18.5 hours. After elevating thetemperature, 400 mL of toluene and 100 mL of saturated aqueous sodiumchloride solution were added, the resulting mixture was separated intolayers, and the organic layer was twice washed with 100 mL portions ofsaturated aqueous sodium chloride solution, dried over anhydrousmagnesium sulfate and filtered. Evaporation of the solvent under reducedpressure gave 20.2 g of the title compound.

¹H NMR(500 MHz, CDCl₃) δ (ppm): 1.90(s, 3H, 10-Me), 5.82(m, 1H, 13-H),6.75(s, 1H, 11-H)

¹³C NMR(125 MHz, CDCl₃) δ (ppm): 138.3(10-C), 141.1(11-C),154.4(12-O—CO—NH₂)

ESI-MS: m/z=870.3[M+H]⁺

Example 31 Preparation of2′-O-benzoyl-3-deoxy-3-oxo-6-O-((3-quinol-3-yl)prop-2-enyl)-5-O-desosaminylerythronolide A 11,12-cyclic Carbamate

To a solution of 2.00 g (2.30 mmol) of the compound obtained in Example30 in 20 mL of tetrahydrofuran was added 28.5 mg (0.230 mmol) of1,5-diazabicyclo[4.3.0]non-5-ene. The resulting mixture was refluxedwith heating for 27 hours. After allowing the mixture to cool, 50 mL ofethyl acetate and 30 mL of saturated aqueous sodium chloride solutionwere added to the mixture, the resulting mixture was separated intolayers, and the aqueous layer was twice extracted with 20 mL portions ofethyl acetate. The organic layers were combined, washed with saturatedaqueous sodium chloride solution, dried over anhydrous magnesiumsulfate, and filtered. Then, the solvent was evaporated under reducedpressure. The resulting concentrated residue was three times purified bysilica gel column chromatography (as the eluent,chloroform:methanol:aqueous ammonia=30:1:0.1 was used once, andacetone:hexane:triethylamine=3:10:0.2−5:10:0.2 was used twice) to obtain1.53 g of the title compound (the same compound as that described inExample 10 of WO 0078773).

Example 32 Preparation of 2′-O-acetyl-9-deoxo-9-hydroxyerythromycin A11,12-cyclic Carbonate

Using ethyl acetate as a solvent, 0.762 g (1.00 mmol) of the compoundobtained in Example 2 was reacted in a similar manner to Example 3. As aresult, 0.74 g of the title compound (the same compound as that obtainedin Example 3) was obtained.

Example 33 Preparation of2′-O-acetyl-9-deoxo-9-hydroxy-6-O-((3-quinol-3-yl)prop-2-enyl)-5-O-desosaminylerythronolide A 11,12-cyclic Carbonate

To a solution of 4.87 g (6.01 mmol) of the compound obtained in Example15 in 73 mL of nitrobenzene was added 0.811 g (6.97 mmol) oft-butyldimethylsilane. After replacing the atmosphere with nitrogen gas,the temperature was lowered to 5° C. Then, 4.1 mL (37.8 mmol) oftitanium tetrachloride was dropwise added thereto over a period of 3minutes. After stirring the resulting mixture for 40 minutes, thereaction solution was poured into a mixture of 35 mL of 28% aqueousammonia and 60 g of ice. After stirring the resulting mixture for 30minutes, the solid matter was filtered off and washed with 150 mL oftoluene. The organic layer was washed three times with 50 mL portions ofsaturated aqueous sodium chloride solution. The toluene was evaporatedunder reduced pressure to obtain a yellow-brown colored solutioncontaining the objective product. Under ice-cooling, 20 mL of 1 mol/Lhydrochloric acid was added to the yellow-brown solution. Afterseparating the resulting mixture into layers, the organic layer wasextracted firstly with 10 mL of 1 mol/L hydrochloric acid and thereafterwith 10 mL of water. The aqueous layers were combined and twice washedwith 10 mL portions of toluene. The aqueous layer thus obtained wasmixed with 0.50 g of active carbon (Norit “SX-II”, manufactured by WakoPure Chemical Industries, Ltd.), and stirred at room temperature for 16hours. After filtering off the active carbon, 17.5 mL of a 2 mol/Laqueous sodium hydroxide solution was added under ice-cooling. Theprecipitate was 70 mL of dissolved in toluene, twice washed with 10 mLportions of saturated aqueous sodium chloride solution, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure. Asa result, 3.71 g of the title compound (the same compound as thatobtained in Example 16) was obtained.

Example 34 Preparation of2′-O-acetyl-6,9-O-acrylidene-9-deoxo-9-hydroxy-5-O-desosaminylerythronolide A 11,12-cyclic Carbonate Tosylate

10.0 g (12.4 mmol) of the compound obtained in Example 3 was dissolvedin 100 mL of chlorobenzene, and a 50 ml fraction of the solvent wasevaporated under atmospheric pressure. Then, 6.53 g (50.2 mmol) ofacrolein diethyl acetal and 3.75 g (14.9 mmol) of pyridiniump-toluenesulfonate were added. After refluxing the resulting mixturewith heating for 5 hours, the mixture was allowed to stand overnight atroom temperature. Then, the precipitate was collected by filtration anddried to obtain 7.15 g of the title compound.

¹H NMR(500 MHz, DMSO-d₆) δ (ppm): 2.06(s, 3H, 2′-OAc), 2.29(s, 3H, CH₃-Ph), 3.67(dd, 1H, J=5.5, 8.0 Hz, 9-H), 4.72(d, 1H, J=7.6 Hz, 1′-H),5.48(d, 1H, J=5.5 Hz, >CH—CH═CH₂)

¹³C NMR(125 MHz, DMSO-d₆) δ (ppm): 20.7(CH₃—Ph), 75.0(3-C), 78.0(6-C),82.1(9-C), 91.5(>CH—CH═CH₂), 98.0(1′-C), 115.3 (>CH—CH═CH₂),169.7(2′-OCOCH₃)

ESI-MS: m/z=706.3[M+Na]⁺

Example 35 Preparation of2′-O-acetyl-6,9-O-acrylidene-9-deoxo-9-hydroxy-5-O-desosaminylerythronolide A 11,12-cyclic Carbonate Tosylate

5.00 g (6.18 mmol) of the compound obtained in Example 3 was dissolvedin 50 mL of chlorobenzene, and a 25 mL fraction of the solvent wasevaporated under the atmospheric pressure. Using 2.56 g (25.2 mmol) ofacrolein dimethyl acetal in place of the acrolein diethyl acetal, areaction was carried out in a similar manner to Example 34 to obtain3.80 g of the title compound (the same compound as that obtained inExample 34).

Example 36 Preparation of2′-O-acetyl-9-deoxo-9-hydroxy-6-O-((3-quinol-3-yl)prop-2-enyl)-5-O-desosaminylerythronolide A 11,12-cyclic Carbonate

5.00 g (6.17 mmol) of the compound obtained in Example 15 was dissolvedin 100 mL of nitrobenzene, and a 50 mL fraction of the solvent wasevaporated under reduced pressure. Under water-cooling, a similarreaction to Example 16 was carried out by using 1.84 g (7.08 mmol) oftriphenylsilane in place of the triethylsilane. As a result, 3.03 g ofthe title compound (the same compound as the compound obtained inExample 16) was obtained.

Example 37 Preparation of2′-O-acetyl-3-deoxy-3-oxo-6-O-((3-quinol-3-yl)prop-2-enyl)-5-O-desosaminylerythronolide A 11,12-cyclic Carbonate

0.70 g (5.50 mmol) of oxalyl chloride was dissolved in 7.5 mL ofdichloromethane, and the atmosphere was replaced with nitrogen gas.After cooling the resulting solution on an acetone-dry ice bath, asolution of 0.859 g (11.0 mmol) of dimethyl sulfoxide in 2.5 mL ofdichloromethane was dropwise added thereto. Then, a solution of 0.41 g(0.500 mmol) of the compound obtained in Example 16 in 2.5 mL ofdichloromethane was dropwise added thereto, and the resulting mixturewas stirred while cooled with acetone-dry ice. Then, 10.2 g (0.10 mmol)of triethylamine was added, and the resulting mixture was stirred whilecooled with acetone-dry ice. Ice and toluene were added to the reactedmixture, and the temperature was elevated to room temperature. Theorganic layer was taken out and washed with saturated aqueous sodiumhydrogen carbonate solution and saturated aqueous sodium chloridesolution, and dried over anhydrous magnesium sulfate. Evaporation of thesolvent under reduced pressure gave 0.39 g of the title compound (thesame compound as the compound obtained in Example 17).

Example 38 Preparation of2′-O-acetyl-9-deoxo-9-hydroxy-6,9-O-(3-(3-quinolyl)acrylidene)-5-O-desosaminylerythronolide A 11,12-cyclic Carbonate

A similar reaction to Example 15 was carried out in a toluene, using0.50 g (0.62 mmol) of the compound obtained in Example 34, 0.14 g (0.68mmol) of 3-bromoquinoline, 0.22 g (0.68 mmol) of tetrabutylammoniumbromide, 0.24 g (1.85 mmol) of diisopropylethylamine and 13.8 mg of 10mol % palladium acetate. Thus, 0.45 g of the title compound (the samecompound as that obtained in Example 15) was obtained.

Example 39 Preparation of2′-O-acetyl-6,9-O-acrylidene-9-deoxo-9-hydroxy-5-O-desosaminylerythronolide A 11,12-cyclic Carbonate Tosylate

0.41 mL (4.35 mmol) of acetic anhydride was added to a solution of 3.02g (3.96 mmol) of the compound obtained in Example 2 in 15 mL ofchlorobenzene. The resulting mixture was stirred at room temperature for2 hours. Subsequently, 2.43 mL (15.9 mmol) of acrolein diethyl acetaland 1.20 g (4.78 mmol) of pyridinium p-toluenesulfonate were added, andthe resulting mixture was heated with stirring at 120° C. for 2.5 hours.Thereafter, the stirring was continued overnight at room temperature.The formed crystals were collected by filtration and washed withchlorotoluene. The crystal thus obtained was dried under reducedpressure at 60° C. for 2 hours to obtain 2.21 g of the title compound(the same compound as that obtained in Example 34).

Examples 40-49 Preparation of2′-O-acetyl-9-deoxo-9-hydroxy-6-O-((3-quinol-3-yl)prop-2-enyl)-5-O-desosaminylerythronolide A 11,12-cyclic Carbonate

Reduction reaction of the compound obtained in Example 15 was carriedout in a similar manner to Example 16 while varying the reactionsolvent, to obtain the title compounds in the following yields.

No. Solvent used in the reaction Yield (%) 40 o-Nitrotoluene 81.3 41Dichlorormethane 73.1 42 Chlorobenzene 76.9 43 Chlorotoluene 67.2 44Fluorobenzene 68.4 45 o-Difluorobenzene 55.1 46 Xylene 55.5 47Acetonitrile 48.8 48 Isopropyl ether 29.2 49 Chlorocyclohexane 56.6

Advantageous Effects of the Invention

According to the present invention, a substituent can easily beintroduced into the hydroxyl group at the 6-position of erythromycin A.The process according to the present invention makes it possible toadvantageously synthesize3-deoxy-3-oxo-6-O-((3-quinol-3-yl)prop-2-enyl)-5-O-desosaminylerythronolide A 11,12-cyclic carbamate or the like.

What is claimed is:
 1. A process for preparing Compound (V) definedbelow, which comprises the steps of: (A) providing Compound (I) of theformula:

wherein R1 and R2, which may be the same or different, are a hydrogenatom, formula —CO—RA wherein RA is a C1-3 alkyl group, C1-3 alkyl groupsubstituted with 1-3 halogen atoms, C1-3 alkoxy group, phenyl group,phenyloxy group, benzyloxy group, or phenyl group substituted with 1-3substituents selected from the group consisting of C1-3 alkyl group,C1-3 alkoxy group, nitro group, cyano group, halogen atom, acetyl group,phenyl group and hydroxy group, or a silyl group substituted with 2-3substituents selected from the group consisting of C1-4 alkyl group,phenyl group and benzyl group, by reaction of erythromycin with ethylenecarbonate, subsequent reduction of ketone in 9-position, and optionalprotection of hydroxy groups in 2′- and/or 4”-positions, (B) reactingCompound (I) with a compound of the formula:

wherein A is CH═CH or C≡C; R5 and R6, which may be the same ordifferent, are a C1-7 alkyl group, and optionally protecting a resulting3-hydroxy group, to obtain Compound (II) of the formula:

wherein R3 is the same as R1 defined above; R2 and A are as definedabove, (C) reacting Compound (II) with a compound of the formula:X—R4  (2) wherein X is a halogen atom; R4 is the formula:

wherein R7 and R8 are a hydrogen atom or, alternatively, they form abenzene nucleus together with the adjacent carbon atoms, or the formula:

wherein Ar is a pyridyl group, quinolyl group or aryl group, to obtainCompound (III) of the formula:

wherein A, R2, R3 and R4 are as defined above, (D) reacting Compound(III) with a compound of the formula:

wherein R9 is a hydrogen atom, chlorine atom, linear or branched C1-4alkyl group, C1-3 alkoxy group, phenyl or benzyl group; R10 and R11,which may be the same or different, are a chlorine atom, linear orbranched C1-4 alkyl group, C1-3 alkoxy group, phenl group or benzylgroup, to obtain Compound (IV) of the formula:

wherein A, R2, R3 and R4 are as defined above, and (E) subjectingCompound (IV) to carbonylation at 9-position, carboxylation at3-position, 11,12-cyclic carbamation and deprotection of 2′-hydroxygroup, to obtain Compound (V) of the formula:

wherein A and R4 are as defined above.
 2. The process according to claim1 wherein the compound of formula (1) is selected from the groupconsisting of acrolein dimethyl acetal, acrolein diethyl acetal,acrolein di-n-propyl acetal, acrolein diisopropyl acetal, acroleindi-n-butyl acetal, acrolein diisobutyl acetal, propiolaldehyde dimethylacetal, propiolaldehyde diethyl acetal, propiolaldehyde di-n-propylacetal, propiolaldehyde diisopropyl acetal, propiolaldehyde di-n-butylacetal and propiolaldehyde diisobutyl acetal.
 3. The process accordingto claim 1 wherein the compound of formula (2) is selected from thegroup consisting of quinolyl chloride, pyridyl chloride, pyridylthienylchloride, quinolyl bromide, pyridyl bromide and pyridylthienyl bromide.4. The process according to claim 1 wherein the compound of formula (3)is selected from the group consisting of trimethylsilane,triethylsilane, trichlorosilane, phenyldimethylsilane, diphenylsilane,triphenylsilane, triethoxysilane, diethylsilane andt-butyldimethylsilane.
 5. A compound of the formula:

wherein A is CH═CH or C≡C; R2 and R3, which may be the same ordifferent, are a hydrogen atom, formula —CO—RA wherein RA is a C1-3alkyl group, C1-3 alkyl group substituted with 1-3 halogen atoms, C1-3alkoxy group, phenyl group, phenyloxy group, benzyloxy group, or phenylgroup substituted with 1-3 substituents selected from the groupconsisting of C1-3 lower alkyl group, C1-3 alkoxy group, nitro group,cyano group, halogen atom, acetyl group, phenyl group and hydroxy group,or a silyl group substituted with 2-3 substituents selected from thegroup consisting of C1-4 alkyl group, phenyl group and benzyl group. 6.A compound of the formula:

wherein A is CH═CH or C≡C; R2 and R3, which may be the same ordifferent, are a hydrogen atom, formula —CO—RA wherein RA is a C1-3alkyl group, C1-3 alkyl group substituted with 1-3 halogen atoms, C1-3alkoxy group, phenyl group, phenyloxy group, benzyloxy group, or phenylgroup substituted with 1-3 substituents selected from the groupconsisting of C1-3 lower alkyl group, C1-3 alkoxy group, nitro group,cyano group, halogen atom, acetyl group, phenyl group and hydroxy group,or a silyl group substituted with 2-3 substituents selected from thegroup consisting of C1-4 alkyl group, phenyl group and benzyl group; R4is the formula:

wherein R7 and R8 are a hydrogen atom or, alternatively, they form abenzene nucleus together with adjacent carbon atoms, or the formula:

wherein Ar is a pyridyl group, quinolyl group or aryl group.
 7. Aprocess for preparing a decladinosylated 6,9-cyclic acetal erythromycinderivative defined below, which comprises the step of reacting Compound(I) of the formula:

wherein R1 and R2, which may be the same or different, are a hydrogenatom, residue —CO—RA in which RA is a C1-3 alkyl group, C1-3 alkyl groupsubstituted with 1-3 halogen atoms, C1-3 alkoxy group, phenyl group,phenyloxy group, benzyloxy group, or phenyl group substituted with 1-3substituents selected from the group consisting of C1-3 alkyl group,C1-3 alkoxy group, nitro group, cyano group, halogen atom, acetyl group,phenyl group and hydroxy group, or a silyl group substituted with 2-3substituents selected from the group consisting of C1-4 alkyl group,phenyl group and benzyl group, with a compound of the formula:

wherein A is CH═CH or C≡C; R5 and R6, which may be the same ordifferent, are a C1-7 alkyl group, to obtain the decladinosylated6,9-cyclic acetal erythromycin derivative of the formula:

wherein R3 is the same as R1 defined above; R2 and A are as definedabove.